This application poses a novel and innovative approach for treatment of acute attacks of hereditary angioedema and potentially for other bradykinin- mediated clinical conditions, such as early gram negative septic shock. We propose a recombinant variant of human C1 inhibitor that will have enhanced activity and that will selectively inhibit kinin generation, but will have diminished reactivity with C1r and C1s. This inhibitor has significant advantages over current treatments: (1) The inhibitor is discriminating and affects the relevant pathway that mediates symptoms, while maintaining the protection afforded by complement. (2) The selectivity also improves efficiency by eliminating competing consumption. (3) The inhibitor will have enhanced activity against surface-bound proteases. (4) A recombinant source of material provides a more defined product with reduced risk of iatrogenic disease compared with current therapy with the plasma derived product. This Phase I feasibility study will produce limited quantities of inhibitor, using a Chinese hamster ovary cell expression system. Purified inhibitor will be tested in vitro to define the inhibition profile. The in vivo activity of the recombinant protein will be tested using a guinea pig skin vascular permeability model, and by interruption of symptoms in C1INH deficient mice. The dose-response effect will be evaluated in comparison with the normal full-length protein. Animal testing will be done to determine plasma half-life and bioavailability. PROPOSED COMMERCIAL APPLICATIONS: The domestic market for treatment of acute angioedema is estimated at 5 million dollars. Treatment for sepsis and other bradykinin-mediated disease would provide access to much larger markets.